US7553969B1 - Substituted phenethylamine derivatives - Google Patents

Substituted phenethylamine derivatives Download PDF

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US7553969B1
US7553969B1 US09/890,219 US89021900A US7553969B1 US 7553969 B1 US7553969 B1 US 7553969B1 US 89021900 A US89021900 A US 89021900A US 7553969 B1 US7553969 B1 US 7553969B1
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tyr
phe
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Hiroharu Matsuoka
Tsutomu Sato
Tadakatsu Takahashi
Dong Ick Kim
Kyung Yun Jung
Chan Hee Park
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Chugai Pharmaceutical Co Ltd
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Chugai Pharmaceutical Co Ltd
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Definitions

  • This invention relates to substituted phenethylamine derivatives that function as a motilin receptor antagonist and that are useful as medicines.
  • Motilin which is one of the gastrointestinal hormones, is a straight-chained peptide consisting of 22 amino acids and is well known to be responsible for regulating the motility of the gastrointestinal tract in animals including human. It has been reported that exogenously administered motilin causes contractions in humans and dogs that are similar to interdigestive migrating contractions, thus promoting gastric emptying (Itoh et al., Scand. J. Gastroenterol., 11, 93-110 (1976); Peeters et al., Gastroenterology 102, 97-101 (1992)). Hence, erythromycin derivatives which are an agonist of motilin are under development as an gastrointestinal tract motor activity enhancer (Satoh et al., J. Pharmacol. Exp. Therap., 271, 574-579 (1994); Lartey et al., J. Med. Chem., 38, 1793-1798 (1995); Drug of the Future, 19, 910-912 (1994)).
  • Motilin receptors had been known to occur principally in the duodenum but recently it has been shown that they also occur in the large intestine, or the lower part of the gastrointestinal tract (William et al., Am. J. Physiol., 262, G50-G55 (1992)), and this indicates the possibility that motilin is involved not only in the motility of the upper part of the gastrointestinal tract but also in the motility of its lower part.
  • An object of the present invention is to provide substituted phenethylamine derivatives that function as an antagonist of motilin receptors and which are useful as medicines.
  • the present inventors conducted repeated intensive studies in an attempt to develop compounds having an outstanding motilin receptor antagonistic action. As a result, they found that substituted phenethylamine derivatives represented by Formula (1) were an excellent antagonist of motilin receptors. The present invention has been accomplished on the basis of this finding.
  • Cy is a group of Formula (2):
  • R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen, halogen, hydroxy, amino, trifluoromethyl or nitrile and at least one of R 1 , R 2 , R 3 , R 4 and R 5 is halogen, trifluoromethyl or nitrile;
  • R 6 is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, amino or hydroxy
  • R 7 is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, optionally substituted amino or hydroxy;
  • R 8 is hydrogen, methyl or ethyl
  • R 9 is optionally substituted straight-chained or branched C 1-6 alkyl, optionally substituted straight-chained or branched C 2-6 alkenyl, optionally substituted straight-chained or branched C 2-6 alkynyl, C 3-7 cycloalkyl or optionally substituted phenyl;
  • R 20 is hydrogen or straight-chained or branched C 1-3 alkyl or R 9 and R 20 may together form C 3-7 cycloalkyl;
  • R 10 is hydrogen or straight-chained or branched C 1-3 alkyl
  • R 11 is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, —CO—N(R 14 )R 15 , carboxyl or an optionally substituted heterocyclic ring;
  • R 12 is hydroxy or —OR 16 ;
  • R 13 is hydrogen, straight-chained or branched C 1-6 alkyl, straight-chained or branched C 2-6 alkenyl, straight-chained or branched C 2-6 alkynyl or a group of Formula (3):
  • R 14 and R 15 which may be the same or different, are hydrogen, optionally substituted straight-chained or branched C 1-4 alkyl, C 3-7 cycloalkyl, straight-chained or branched C 1-4 alkyloxy, straight-chained or branched C 1-4 alkylsulfonyl or a heterocyclic ring, or R 14 and R 15 , as —N(R 14 )R 15 , form optionally substituted 3- to 7-membered cyclic amine;
  • R 16 is straight-chained C 1-4 alkyl
  • R 17 is hydrogen or methyl
  • R 18 and R 19 together form cycloalkyl or C 3-7 cycloalkenyl
  • X is carbonyl or methylene
  • Y is carbonyl or methylene
  • R 11 is an optionally substituted heterocyclic ring
  • the present invention also provides a medicine containing a compound of Formula (1) as an active ingredient. Further, the present invention provides a motilin receptor antagonist composition containing the compound. The present invention also provides a gastrointestinal motility suppressor agent containing the compound as an active ingredient. Further, the present invention provides a therapeutic of hypermotilinemia containing the compound as an active ingredient.
  • the present invention also provides compounds of Formula (4):
  • R 7 ′ is hydrogen, straight-chained or branched C 1-3 alkyl optionally having at least one protected substituent, amino optionally having at least one protected substituent or protected hydroxy;
  • R 11 ′′ is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, —CO—N(R 14 )R 15 , wherein R 14 and R 15 are as defined in claim 1 , carboxyl, straight-chained or branched C 1-3 alkyl having protected amino or an optionally substituted heterocyclic ring;
  • the present invention also provides compounds of Formula (5):
  • R 7 ′′ is hydrogen, straight-chained or branched C 1-3 alkyl optionally having at least one optionally protected substituent, amino optionally having at least one optionally protected substituent or optionally protected hydroxy;
  • R 11 ′ is hydrogen, straight-chained or branched C 1-3 alkyl optionally having at least one protected substituent, —CO—N(R 14 )R 15 wherein R 14 and R 15 are as defined in claim 1 , carboxyl or an optionally substituted heterocyclic ring; or hydrates or pharmaceutically acceptable salts thereof.
  • the present invention also provides compounds of Formula (6):
  • R 8 , R 9 , R 20 , R 10 , R 12 , R 13 and Y are as defined in claim 1 ;
  • P 1 is hydrogen or a protecting group of amine
  • R 11 ′′′ is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, —CO—N(R 14 )R 15 wherein R 14 and R 15 are as defined in claim 1 , carboxyl, straight-chained or branched C 1-3 alkyl having protected amino or an optionally substituted heterocyclic ring;
  • the present invention also provides compounds of Formula (7):
  • R 7 ′′ is hydrogen, straight-chained or branched C 1-3 alkyl optionally having at least one optionally protected substituent, amino optionally having at least one optionally protected substituent or optionally protected hydroxy;
  • P 2 is optionally protected carboxyl, formyl or methyl having a leaving group
  • the present invention also provides compounds of Formula (8)
  • R 10 and R 13 are as defined in claim 1 ;
  • P 3 is hydrogen or a protecting group of amine
  • R 11 ′′′′ is hydrogen, optionally substituted straight-chained or branched C 1-3 alkyl, —CO—N(R 14 )R 15 wherein R 14 and R 15 are as defined in claim 1 , carboxyl, straight-chained or branched C 1-3 alkyl having protected amino or an optionally substituted heterocyclic ring;
  • R 12 ′ is hydroxy or —OR 16 , wherein R 16 is as defined in claim 1 ;
  • the present invention also provides compounds of Formula (9)
  • R 7 ′′ is hydrogen, straight-chained or branched C 1-3 alkyl optionally having at least one optionally protected substituent, amino optionally having at least one optionally protected substituent or optionally protected hydroxy;
  • P 4 is optionally protected carboxyl, formyl or methyl having a leaving group
  • the present invention also provides compounds of Formula (10)
  • R 8 , R 9 and R 20 are as defined in claim 1 ;
  • P 5 is hydrogen or a protecting group of amine
  • P 6 is optionally protected carboxyl, formyl or methyl having a leaving group
  • halogen as R 1 , R 2 , R 3 , R 4 and R 5 of Formula (2) as Cy is preferably fluorine or chlorine, with fluorine being more preferred.
  • R 1 to R 5 are halogen, they may be the same or different halogen, however it is preferable that they are the same.
  • the number of halogen atoms is preferably 1 to 3 and more preferably 1 or 2.
  • At least one of R 1 , R 2 , R 3 , R 4 and R 5 of Formula (2) as Cy is halogen, trifluoromethyl or nitrile and the others are independently hydrogen or hydroxy.
  • R 3 is halogen, trifluoromethyl or nitrile or R 2 and R 3 are the same kind of halogen.
  • Preferred compounds include those in which R 3 is halogen and R 1 , R 2 , R 4 and R 5 are hydrogen; those in which R 2 and R 3 are the same halogen and R 1 , R 4 and R 5 are hydrogen; and those in which at least one of R 1 , R 2 , R 3 , R 4 and R 5 is trifluoromethyl or nitrile and the others are hydrogen, halogen or hydroxy.
  • Preferred examples of the group of Formula (2) as Cy include 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 4-trifluoromethylphenyl and 4-cyanophenyl, more preferably 4-fluorophenyl and 4-chlorophenyl, with 4-fluorophenyl being most preferred.
  • heterocyclic ring of the optionally substituted heterocyclic ring as Cy include aliphatic or aromatic 5- to 7-membered mono- or fused-rings containing at least one hetero atom selected from among N, S and O; specific examples include pyridyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, indolyl, quinolinyl, benzoimidazolyl, benzodiazepinyl, benzofuryl, pyrrolidinyl, piperazinyl, piperidinyl and tetrahydroisoquinolinyl, with indolyl being preferred.
  • Exemplary substituents of the optionally substituted heterocyclic ring as Cy include hydroxy, methoxy, amino, methyl, ethyl, trifluoromethyl, carboxy, methoxycarbonyl and oxo.
  • the heterocyclic ring may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted heterocyclic ring of Cy is 3-indolyl.
  • the C 3-7 cycloalkyl as Cy is cyclopentyl or cyclohexyl.
  • Cy has the definitions set forth above, Cy is preferably Formula (2) or an optionally substituted heterocyclic ring, more preferably 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl and 3-indolyl, with 4-fluorophenyl being particularly preferred.
  • the alkyl of the optionally substituted straight-chained or branched C 1-3 alkyl as R 6 is preferably methyl or ethyl.
  • Exemplary substituents of the optionally substituted straight-chained or branched C 1-3 alkyl as R 6 include halogen, with fluorine being preferred.
  • the alkyl may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted straight-chained or branched C 1-3 alkyl as R 6 is preferably methyl, ethyl, fluoromethyl or trifluoromethyl, with methyl being particularly preferred.
  • R 6 has the definitions set forth above, R 6 is preferably hydrogen or methyl.
  • the alkyl of the optionally substituted straight-chained or branched C 1-3 alkyl as R 7 is preferably methyl.
  • substituents of the optionally substituted straight-chained or branched C 1-3 alkyl as R 7 include halogen, hydroxy and amino, with hydroxy being preferred.
  • the alkyl may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted straight-chained or branched C 1-3 alkyl as R 7 is preferably methyl or trifluoromethyl, with methyl being particularly preferred.
  • Exemplary substituents of the optionally substituted amino as R 7 include straight-chained or branched C 1-3 alkyl, with methyl and ethyl being preferred.
  • the amino may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted amino as R 7 is preferably amino optionally substituted with one or more of the same or different kinds of straight-chained or branched C 1-3 alkyl; specific examples include amino, methylamino, dimethylamino and ethylamino, with amino and methylamino being particularly preferred.
  • R 7 has the definitions set forth above, R 7 is preferably hydrogen or optionally substituted amino, with hydrogen, amino and methylamino being particularly preferred.
  • R 8 is preferably hydrogen or methyl.
  • the alkyl of the optionally substituted straight-chained or branched C 1-6 alkyl as R 9 is preferably straight-chained or branched C 1-5 alkyl, e.g., methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl and neopentyl.
  • substituents of the optionally substituted straight-chained or branched C 1-6 alkyl as R 9 include substituted or unsubstituted phenyl (e.g., phenyl, tolyl, para-hydroxyphenyl and para-fluorophenyl), C 3-7 cycloalkyl, heterocyclic rings (e.g., pyrazyl, furyl, thienyl, pyrrolyl, imidazolyl and quinolinyl) and halogen, with phenyl, cyclohexyl and thienyl being preferred.
  • phenyl e.g., phenyl, tolyl, para-hydroxyphenyl and para-fluorophenyl
  • C 3-7 cycloalkyl e.g., pyrazyl, furyl, thienyl, pyrrolyl, imidazolyl and quinolinyl
  • halogen e.g., phenyl,
  • the optionally substituted straight-chained or branched C 1-6 alkyl as R 9 is preferably methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, neopentyl, para-fluorobenzyl, 2-thienylmethyl, 3-indolylmethyl, benzyl, para-hydroxybenzyl, phenethyl or cyclohexylmethyl.
  • the alkenyl of the optionally substituted straight-chained or branched C 2-6 alkenyl as R 9 is preferably vinyl, 2-propenyl, 2-propen-1-yl, 2-buten-1-yl or 2-isobuten-1-yl, with 2-propen-1-yl being more preferred.
  • Exemplary substituents of the optionally substituted straight-chained or branched C 2-6 alkenyl as R 9 include phenyl, tolyl, para-hydroxyphenyl and para-fluorophenyl.
  • the optionally substituted straight-chained or branched C 2-6 alkenyl as R 9 is preferably 2-propen-1-yl.
  • the alkynyl of the optionally substituted straight-chained or branched C 2-6 alkynyl as R 9 is preferably ethynyl, propargyl or 2-butyn-1-yl, with 2-butyn-1-yl being preferred.
  • substituents of the optionally substituted straight-chained or branched C 2-6 alkynyl as R 9 include halogen, phenyl, tolyl, para-hydroxyphenyl and para-fluorophenyl.
  • the optionally substituted straight-chained or branched C 2-6 alkynyl as R 9 is preferably 2-butyn-1-yl.
  • the C 3-7 cycloalkyl as R 9 is preferably cyclopentyl or cyclohexyl.
  • Exemplary substituents of the optionally substituted phenyl as R 9 include hydroxy, amino, methyl, ethyl and halogen.
  • the phenyl may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted phenyl as R 9 is preferably phenyl.
  • the C 3-7 cycloalkyl formed by R 9 and R 20 is preferably cyclopentyl or cyclohexyl.
  • R 9 has the definitions set forth above, R 9 is preferably isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, neopentyl, cyclohexyl, 2-thienylmethyl, 3-indolylmethyl, phenyl, benzyl, para-hydroxybenzyl, para-fluorobenzyl or cyclohexylmethyl, with isopropyl being particularly preferred.
  • the straight-chained or branched C 1-3 alkyl as R 20 is preferably methyl.
  • R 20 is preferably hydrogen.
  • R 10 is preferably hydrogen or methyl.
  • the alkyl of the optionally substituted straight-chained or branched C 1-3 alkyl as R 11 is preferably methyl.
  • substituents of the optionally substituted straight-chained or branched C 1-3 alkyl as R 11 include amino optionally substituted with one or more of the same or different kind of straight-chained or branched C 1-3 alkyl (e.g., amino, methylamino, dimethylamino and ethylamino), optionally substituted 3- to 7-membered cyclic amino (exemplary substituents of the cyclic amino include hydroxy, amino, carboxyl, carbamoyl and methyl), hydroxy, methoxy, halogen, carbamoyl, methanesulfonyl, ureide, guanidyl, N′-cyano-N′′-methylguanidyl, sulfamoylamino, carbamoylmethylamino and methanesulfonylamino, with amino, hydroxy, carbamoyl, methanesulfonyl, ureide, sulfamoyla
  • the optionally substituted straight-chained or branched C 1-3 alkyl as R 11 is preferably methyl, aminomethyl, hydroxymethyl, carbamoylmethyl, methanesulfonylmethyl, ureidemethyl, guanidylmethyl, sulfamoylaminomethyl or methanesulfonylaminomethyl, with methyl, hydroxymethyl and methanesulfonylmethyl being more preferred.
  • the alkyl of the optionally substituted straight-chained or branched C 1-4 alkyl as R 14 and R 15 of —CO—N(R 14 )R 15 as R 11 is preferably methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl or tert-butyl, with methyl and ethyl being more preferred.
  • Exemplary substituents of the optionally substituted straight-chained or branched C 1-4 alkyl as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 include optionally substituted straight-chained or branched C 1-3 alkoxy (exemplary substituents of the optionally substituted straight-chained or branched C 1-3 alkoxy include hydroxy, amino, carboxyl and carbamoyl), hydroxy, amino, methylamino, dimethylamino, carbamoyl and methanesulfonyl, with hydroxy, methoxy and methanesulfonyl being preferred.
  • Examples of the optionally substituted straight-chained or branched C 1-4 alkyl as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 include methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, methoxymethyl, 2-hydroxyethyl, 2-aminoethyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 2-amino-2-methylpropyl and methanesulfonylmethyl, with methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, methoxymethyl and methanesulfonylmethyl being preferred.
  • the C 3-7 cycloalkyl as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 is preferably cyclopropyl.
  • the straight-chained or branched C 1-4 alkyloxy as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 is preferably methoxy.
  • the straight-chained or branched C 1-4 alkylsulfonyl as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 is preferably methanesulfonyl.
  • heterocyclic ring as R 14 and R 15 in —CO—N(R 14 )R 15 as R 11 include aliphatic or aromatic 5- or 6-membered rings containing at least one hetero atom selected from among N, S and O; specific examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl and triazolyl, with 2-pyridyl being preferred.
  • the 3- to 7-membered cyclic amine of the optionally substituted 3- to 7-membered cyclic amine as —N(R 14 )R 15 as R 11 include aziridine, azetidine, pyrrolidine, piperidine, piperazine and morpholine, with piperazine and morpholine being preferred.
  • Exemplary substituents of the optionally substituted 3- to 7-membered cyclic amine include hydroxy, amino, carboxyl, alkoxycarbonyl, carbamoyl, methyl, carboxymethyl, alkoxycarbonylmethyl and methylsulfonyl.
  • the optionally substituted 3- to 7-membered cyclic amine as —N(R 14 )R 15 of —CO—N(R 14 )R 15 as R 11 is preferably 4-carboxymethylpiperazine, 4-ethoxycarbonylpiperazine, 4-methylsulfonylpiperazine or morpholine.
  • the —CO—N(R 14 )R 15 as R 11 is preferably carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, tert-butylcarbamoyl, 2-pyridylcarbamoyl, methanesulfonylmethylcarbamoyl, 4-ethoxycarbonylmethyl-1-piperazinecarbonyl, methoxymethylcarbamoyl, methoxycarbamoyl, 1-morpholinylcarbonyl, 4-carboxymethyl-1-piperazinecarbonyl and 4-methylsulfonyl-1-piperazinecarbonyl, with carbamoyl and ethylcarbamoyl being more preferred.
  • heterocyclic ring of the optionally substituted heterocyclic ring as R 11 examples include aliphatic or aromatic 5- or 6-membered rings containing at least one hetero atom selected from among N, S and O.
  • exemplary substituents of the heterocyclic ring include oxo, hydroxy, methyl, ethyl and trifluoromethyl; the heterocyclic ring may have one or more of the above-mentioned substituents, which may be the same or different.
  • the optionally substituted heterocyclic ring include furyl, thienyl, pyrrolyl, oxazolyl, 2-thiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-triazol-2-yl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 4-pyrimidinon-2-yl, 6-methyl-4-pyrimidinon-2-yl and imidazolidine-2,4-dion-5-yl, with 2-thiazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-triazol-2-yl and 6-methyl-4-pyrimidino-2-yl being preferred.
  • R 11 is preferably methyl, hydroxymethyl, carbamoylmethyl, methanesulfonylmethyl, ureidemethyl, sulfamoylaminomethyl, methanesulfonylaminomethyl, carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, tert-butylcarbamoyl, 2-pyridylcarbamoyl, methanesulfonylmethylcarbamoyl, 4-ethoxycarbonylmethyl-1-piperazinecarbonyl, methoxymethylcarbamoyl, methoxycarbamoyl, 1-morpholinylcarbonyl, 4-carboxymethyl-1-piperazinecarbonyl, 4-methylsulfonyl-1-piperazinecarbonyl,
  • the straight-chained C 1-4 alkyl as R 16 of —OR 16 as R 12 is preferably methyl.
  • R 12 is preferably hydroxy.
  • the straight-chained or branched C 1-6 alkyl as R 13 is preferably straight-chained or branched C 2-5 alkyl, more preferably branched C 3-5 alkyl, and most preferably tert-butyl.
  • the straight-chained or branched C 2-6 alkenyl as R 13 is preferably straight-chained or branched C 3-5 alkenyl and more preferably branched C 3-5 alkenyl.
  • the straight-chained or branched C 2-6 alkynyl as R 13 is preferably straight-chained or branched C 3-5 alkynyl and more preferably branched C 3-5 alkynyl.
  • R 17 in Formula (3) as R 13 is preferably methyl.
  • the C 3-7 cycloalkyl formed by R 18 and R 19 in Formula (3) as R 13 is preferably C 3-5 cycloalkyl.
  • the C 3-7 cycloalkenyl formed by R 18 and R 19 in Formula (3) as R 13 is preferably C 3-5 cycloalkenyl.
  • R 13 has the definitions set forth above, R 13 is preferably isopropyl, tert-butyl, 1,1-dimethylpropyl and 1,1-dimethyl-2-propenyl, with tert-butyl being more preferred.
  • X is preferably carbonyl or methylene.
  • Y is preferably carbonyl or methylene.
  • Cy is a group of Formula (2) in which at least one of R 1 , R 2 , R 3 , R 4 and R 5 is halogen and the others are hydrogen or hydroxy;
  • R 6 is hydrogen or methyl;
  • R 7 is hydrogen or optionally substituted amino;
  • R 8 is hydrogen or methyl;
  • R 9 is methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-pentyl, neopentyl, cyclohexyl, phenyl, benzyl, para-hydroxybenzyl, para-fluorobenzyl or cyclohexylmethyl;
  • R 20 is hydrogen;
  • R 10 is hydrogen or methyl;
  • R 11 is methyl, hydroxymethyl, carbamoylmethyl, methanesulfonylmethyl, ureidemethyl, sulfamoylaminomethyl, methanesulfonylaminomethyl, carbamoyl, methylcar
  • More preferred compounds are Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(3,4-F 2 )-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe, 2-((2-amino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethyl
  • Particularly preferred compounds are Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(4-Cl)-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe(3,4-F 2 )-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 , N-Me-Phe(4-F)-N-Me-Val-Tyr(3-tBu)-NHEt, 2-((2-amino-3-(4-fluorophenyl)propionyl)-N-methylamino)-3-methylbutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethylamide, 2-((2-amino-3-(4-fluorophenyl)propionyl)-N-methylamino
  • Examples of the protecting groups of the protected substituent of the straight-chained or branched C 1-3 alkyl as R 7 ′ include those which are known as useful protecting groups of amino or hydroxy; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl, benzyloxymethyl, t-butyl and tetrahydropyranyl.
  • Examples of the protecting groups of the protected substituent of the amino as R 7 ′ include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the protected hydroxy include those which are known as useful protecting groups of hydroxy; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, trimethylsilyl, t-butyldimethylsilyl, benzyl, benzyloxymethyl, t-butyl and tetrahydropyranyl.
  • Examples of the protecting groups of the protected amino of the straight-chained or branched C 1-3 alkyl as R 11 ′′ include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the optionally protected substituent of the straight-chained or branched C 1-3 alkyl as R 7 ′′ include those which are known as useful protecting groups of amino or hydroxy; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl, benzyloxymethyl, t-butyl and tetrahydropyranyl.
  • Examples of the protecting groups of the optionally protected substituent of the amino as R 7 ′′ include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the optionally protected hydroxy as R 7 ′′ include those which are known as useful protecting groups of hydroxy; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, trimethylsilyl, t-butyldimethylsilyl, benzyl, benzyloxymethyl, t-butyl and tetrahydropyranyl.
  • Examples of the protecting groups of the protected substituent of the straight-chained or, branched C 1-3 alkyl as R 11 ′ include those which are known as useful protecting groups of amino or hydroxy; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl, benzyloxymethyl, t-butyl and tetrahydropyranyl.
  • Examples of the protecting groups of amine as P 1 include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the protected amino of the straight-chained or branched C 1-3 alkyl as R 11 ′′′ include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the optionally protected carboxyl as P 2 include those which are known as useful protecting groups of carboxyl; specific examples are methyl, ethyl, t-butyl, allyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl and t-butyldimethylsilyl.
  • Examples of the protecting groups of amine as P 3 include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the protected amino of the straight-chained or branched C 1-3 alkyl as R 11 ′′′′ include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the optionally protected carboxyl as P 4 include those which are known as useful protecting groups of carboxyl; specific examples are methyl, ethyl, t-butyl, allyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl and t-butyldimethylsilyl.
  • Examples of the protecting groups of amine as P 5 include those which are known as useful protecting groups of amino; specific examples are benzyloxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, benzoyl, acetyl, trifluoroacetyl, benzenesulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, benzyl and benzyloxymethyl.
  • Examples of the protecting groups of the optionally protected carboxyl as P 6 include those which are known as useful protecting groups of carboxyl; specific examples are methyl, ethyl, t-butyl, allyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl and t-butyldimethylsilyl.
  • Salt-forming acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid and trifluoroacetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid and trifluoroacetic acid.
  • the compounds of the present invention can occur as optical isomers and the respective optical isomers and mixtures thereof are all included within the scope of the invention.
  • the compounds of the present invention can also be obtained as hydrates.
  • a and B in Formulae (I) to (III) are functional groups which can form a bond by the reaction with amino; specific examples are carboxyl, formyl, halomethylene of which halogen is chlorine, bromine or iodine, and sulfonyloxymethylene of which sulfonyl is methanesulfonyl, trifluoromethanesulfonyl, paratoluenesulfonyl and the like.
  • R 1 to R 10 , R 12 and R 13 are as defined above, provided that when they are reactive groups such as amino, hydroxy or carboxyl, they are protected by normally used appropriate protecting groups, if desired.
  • R 11 is as defined above or is a functional group which is convertible to one of the above defined groups.
  • the compounds of Formula (1) may be produced by first binding Compound (II) and Compound (III), optionally followed by deprotection, and then binding the resultant compound with Compound (i), optionally followed by deprotection or conversion of the functional group(s).
  • the compound of Formula (1) may be produced by first binding Compound (I) and Compound (II), optionally followed by deprotection, and then binding the resultant compound with Compound (III), optionally followed by deprotection or conversion of the functional group(s).
  • the compounds of the present invention may be produced by either the solid-phase process or the liquid-phase process.
  • an automatic organic synthesizer can be used but it may be replaced by the manual procedure.
  • Compound (I) if it has a functional group such as amino and hydroxy, with the functional group being protected, is carboxylic acid (A is —CO 2 H), aldehyde (A is —CHO), alkylhalide (A is —CH 2 -Hal), sulfonate (A is —CH 2 —OSO 2 R) or the like. In this case, bond can be formed by reacting A of Compound (I) with the amino group of Compound (II).
  • Compound (II) can, in almost all cases, be derived from an ⁇ -amino acid and B is carboxyl (—CO 2 H), formyl (—CHO), halomethyl (—CH 2 -Hal), sulfonyloxymethyl (RSO 2 O—CH 2 —) or the like.
  • the amino group of Compound (II) is reacted with A of Compound (I) to form bond and B of Compound (II) is reacted with the amino group of Compound (III) to form bond.
  • Compound (III) is an ethylamine derivative and can be generally derived from an amino acid. The amino group of Compound (III) is reacted with B of Compound (II) to form bond.
  • a or B is carboxyl
  • various methods known in peptide synthesis may be used to activate the carboxyl for condensation with the amino group and such methods include the use of benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), the use of PyCIU, the use of bromo tripyrrolidino phosphonium hexafluorophosphate (PyBrop), the use of chlorotripyrrolidino phosphonium hexafluorophosphate (PyClop), the use of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), the use of DIC, the use of N-ethyl-N′-3-dimethylaminopropyl carbodilmide (WSCI), the use of dicyclohexyl carbodiimide (DCC), the use of diphen
  • bond can be formed by conventional reductive bond forming reaction with amino group.
  • bond can be formed by substitution reaction with amino group.
  • the compounds of the present invention can also be produced by applying the specific methods of production to be described in the following Examples.
  • MA SHIMADZU GCMS-QP5050A or SHIMADZU GCMS-QP1000.
  • Reaction time means stirring time
  • Cold sol means the eluting solvent for silica gel column chromatography
  • the retention time (min.) on HPLC is measured under the following conditions:
  • N-(2-(benzyloxycarbonylamino)-3-(3-tBu-4-hydroxyphenyl)propyl)urea 0.9 g, 2.26 mmol
  • 10% palladium carbon 100 mg was added and stirred in a hydrogen atmosphere at room temperature for 12 hours. After filtration, the filtrate was concentrated under reduced pressure to give N-(2-amino-3-(3-tBu-4-hydroxyphenyl)propyl)urea (0.54 g).
  • the reaction mixture was mixed with a saturated aqueous NaHCO 3 solution, extracted with ethyl acetate and washed with saturated brine.
  • reaction mixture was mixed with water and extracted with ethyl acetate.
  • organic layer was dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure.
  • N-[3-(4-benzyloxy-3-tert-butylphenyl)-2-benzyloxycarbonylaminopropyl]methanesulfonamide (1.2 g, 2.29 mmol) was dissolved in a mixture of methanol (23 ml) and methylene chloride (5 ml), mixed with palladium hydroxide/carbon (0.60 g) and stirred for 12 hours in a hydrogen atmosphere. After filtering off insoluble material using Celite, the filtrate was concentrated to give crude N-[2-amino-3-(4-benzyloxy-3-tert-butylphenyl)propyl]methanesulfonamide (0.68 g).
  • lithium aluminum hydride 120 mg, 3.16 mmol was added at ⁇ 10° C. and stirred at the same temperature for 10 min.
  • the reaction mixture was mixed with 15 ml of a solution of potassium hydrogen sulfate (630 mg, 4.63 mmol).
  • the reaction mixture was extracted with ethyl acetate.
  • Boc-Phe(4-F)-OH 63 mg, 0.222 mmol
  • 2-[2-(3-tert-butyl-4-hydroxyphenyl)-1-(3-methyl-2-methylaminobutyrylamino)ethyl]-6-methyl-4-pyrimidinone (B) 77 mg, 0.185 mmol
  • CMPI 57 mg, 0.222 mmol
  • THF 5 ml
  • TEA 0.08 ml, 0.573 mmol
  • reaction mixture was filtered and the filtrate was concentrated under reduced pressure; to a solution of the thus obtained residue in THF (13 ml), Z-N-Me-Val-OH (509 mg, 1.92 mmol), CMPI (491 mg, 1.92 mmol) and TEA (0.535 ml, 3.84 mmol) were added under cooling with ice and stirred at room temperature for 3 hours.
  • the reaction mixture was mixed with water and extracted with ethyl acetate.
  • the reaction mixture was mixed with water and extracted with ethyl acetate.
  • the reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure.
  • the reaction mixture was evaporated to remove the solvent under reduced pressure; the thus obtained residue was mixed with methylene chloride, washed with a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure.
  • Example 1 (5) “(Example 17)” and “(Example 10)” mean that the methods of preparing the compounds are described in the corresponding Examples 1 (5), 17 and 10, respectively.
  • “Commercial” means that the compound is commercially available.
  • N-Me-Tyr(3-tBu)-QMe 8.20 g, 31.1 mmol
  • methanol 20 ml
  • a 30% methylamine methanol solution 200 ml
  • Boc-Phe(4-F)-OH (13.4 g, 47.3 mmol) in THF (100 ml)
  • 60% sodium hydride (5.7 g, 142 mmol)
  • methyl iodide (23.6 ml, 378 mmol) were added under cooling with ice.
  • the mixture was stirred at room temperature for 38 hours, under cooling with ice, mixed with water and washed with n-hexane. Under cooling with ice, the aqueous layer was rendered acidic by 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure.
  • the thus obtained residue was mixed with ether and n-hexane and the thus formed precipitate was collected by filtration to give Boc-N-Me-Phe(4-F)-OH(P2) (11.4 g, 81%).
  • Scheme 1 shows the synthesis scheme of Examples 28-64.
  • Scheme 2 shows the synthesis scheme of Examples 65-78.
  • Reaction 4a Compound Reaction I-c20 Pd(OH) 2 MeOH time
US09/890,219 1999-01-28 2000-01-28 Substituted phenethylamine derivatives Expired - Fee Related US7553969B1 (en)

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US10201614B2 (en) 2013-03-15 2019-02-12 Zymeworks Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
US10278957B2 (en) 2017-09-11 2019-05-07 Protagonist Therapeutics, Inc. Opioid agonist peptides and uses thereof
US10450378B2 (en) 2014-09-17 2019-10-22 Zymeworks Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
CN111094238A (zh) * 2017-07-31 2020-05-01 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途
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US20090137835A1 (en) * 2003-06-18 2009-05-28 Tranzyme Pharma Inc. Processes for intermediates for macrocyclic compounds
US20090240027A1 (en) * 2003-06-18 2009-09-24 Tranzyme Pharma Inc. Intermediates for macrocyclic compounds
US8129561B2 (en) 2003-06-18 2012-03-06 Tranzyme Pharma Inc. Processes for intermediates for macrocyclic compounds
US8497242B2 (en) 2003-06-18 2013-07-30 Tranzyme Pharma Inc. Processes for intermediates for macrocyclic compounds
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
US10040751B2 (en) 2003-06-18 2018-08-07 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
US10201614B2 (en) 2013-03-15 2019-02-12 Zymeworks Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
US11617777B2 (en) 2013-03-15 2023-04-04 Zymeworks Bc Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
US11560422B2 (en) 2013-12-27 2023-01-24 Zymeworks Inc. Sulfonamide-containing linkage systems for drug conjugates
US10450378B2 (en) 2014-09-17 2019-10-22 Zymeworks Inc. Cytotoxic and anti-mitotic compounds, and methods of using the same
CN111094238A (zh) * 2017-07-31 2020-05-01 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途
CN111094238B (zh) * 2017-07-31 2023-06-09 杰资制药爱尔兰有限公司 氨基甲酰基苯丙氨醇类似物及其用途
US10278957B2 (en) 2017-09-11 2019-05-07 Protagonist Therapeutics, Inc. Opioid agonist peptides and uses thereof
US10729676B2 (en) 2017-09-11 2020-08-04 Protagonist Theraputics, Inc. Opioid agonist peptides and uses thereof

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WO2000044770A1 (fr) 2000-08-03
JP3715202B2 (ja) 2005-11-09
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HUP0105204A2 (hu) 2002-04-29
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